AMPD2 — Adenosine Monophosphate Deaminase 2

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AMPD2 Gene

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AMPD2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">AMPD2 — Adenosine Monophosphate Deaminase 2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>AMPD2</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Adenosine Monophosphate Deaminase 2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>AMPD2, AMPD2, Adenosine Monophosphate Deaminase 2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>271</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q01469</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000116337</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>102771</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>AMP deaminase family</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>AMP</td>
</tr>
<tr>
<td class="label">Product</td>
<td>IMP + NH3</td>
</tr>
<tr>
<td class="label">Km (AMP)</td>
<td>50-200 μM</td>
</tr>
<tr>
<td class="label">Vmax</td>
<td>High</td>
</tr>
<tr>
<td class="label">pH optimum</td>
<td>6.5-7.5</td>
</tr>
<tr>
<td class="label">Activators</td>
<td>ATP, GTP (at high conc.)</td>
</tr>
<tr>
<td class="label">Inhibitors</td>
<td>IMP (feedback)</td>
</tr>
<tr>
<td class="label">Mutation Type</td>
<td>Examples</td>
</tr>
<tr>
<td class="label">Missense</td>
<td>p.R475H, p.P580L</td>
</tr>
<tr>
<td class="label">Nonsense</td>
<td>p.R213X, p.W553X</td>
</tr>
<tr>
<td class="label">Frameshift</td>
<td>c.1653delC</td>
</tr>
<tr>
<td class="label">Splice site</td>
<td>c.2080+1G>A</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Findings</td>
</tr>
<tr>
<td class="label">AMPD2 knockout mice</td>
<td>Spastic phenotype, TCC thinning</td>
</tr>
<tr>
<td class="label">Patient iPSC neurons</td>
<td>Elevated AMP, mTORC1 activation</td>
</tr>
<tr>
<td class="label">Knock-in models</td>
<td>Variable severity based on mutation</td>
</tr>
<tr>
<td class="label">Protein/Pathway</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">AMPK</td>
<td>Via AMP/ATP ratio</td>
</tr>
<tr>
<td class="label">mTORC1</td>
<td>Via AMPK</td>
</tr>
<tr>
<td class="label">TSC complex</td>
<td>Direct interaction</td>
</tr>
<tr>
<td class="label">IMP dehydrogenase</td>
<td>Sequential pathway</td>
</tr>
<tr>
<td class="label">5'-nucleotidase</td>
<td>Sequential pathway</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">24 edges</a></td>
</tr>
</table>

Overview

Mermaid diagram (expand to render)

AMPD2 (Adenosine Monophosphate Deaminase 2) encodes a critical enzyme in purine nucleotide metabolism that catalyzes the deamination of adenosine monophosphate (AMP) to inosine monophosphate (IMP), a key step in the adenine nucleotide catabolic pathway["@novarino2014"][@wang2020]. This enzyme plays essential roles in cellular energy homeostasis, mTORC1 signaling regulation, and has emerged as an important player in neurodegenerative diseases, particularly hereditary spastic paraplegia (HSP) type 63 (SPG63).

The AMPD2 gene produces the muscle (M) isoform of AMP deaminase, which is predominantly expressed in skeletal muscle, heart, and brain. The enzyme functions as a homotetramer and is localized primarily in the cytosol, where it serves as a crucial node in the adenine nucleotide metabolism network. Loss-of-function mutations in AMPD2 cause autosomal recessive hereditary spastic paraplegia type 63, characterized by progressive lower limb spasticity and often accompanied by thin corpus callosum and cognitive impairment.

Beyond its role in HSP, AMPD2 has attracted significant attention due to its involvement in regulating the mTORC1 signaling pathway—a central regulator of cell growth, metabolism, and autophagy. Through its enzymatic activity and downstream effects on AMPK (AMP-activated protein kinase), AMPD2 influences cellular energy sensing and the balance between anabolism and catabolism. This positions AMPD2 as a potential therapeutic target not only for HSP but also for other neurodegenerative conditions involving mTORC1 dysregulation, including tuberous sclerosis complex, and for certain metabolic disorders.

Gene Information

Protein Structure and Function

Enzyme Classification

AMPD2 belongs to the amidohydrolase family of enzymes, specifically the AMP deaminase family. The enzyme catalyzes the following reaction:

AMP + H2O → IMP + NH3

This reaction is part of the purine nucleotide cycle and plays crucial roles in:

Energy homeostasis: Regulation of adenine nucleotide pool

mTORC1 signaling: Through modulation of AMP/ATP ratio

Amino acid metabolism: Links to aspartate biosynthesis

Structural Features

The AMPD2 protein (~771 amino acids, ~85 kDa) possesses:

N-terminal domain: Catalytic core containing the active site
C-terminal domain: Regulatory region with allosteric binding sites
Tetramerization interface: Forms functional homotetramers
AMP binding site: High-affinity binding for substrate
Allosteric sites: Binding for ATP, GTP, and IMP (feedback inhibition)

Catalytic Properties

Expression Pattern

Tissue Distribution

AMPD2 exhibits broad expression with highest levels in:

Skeletal muscle: Highest expression, dominant isoform
Heart: Significant expression
Brain: Particularly high in neurons
Liver: Moderate expression
Kidney: Present in tubular cells

Cellular Distribution in the Brain

In the central nervous system:

[Neurons](/entities/neurons): High expression in cerebral cortex, hippocampus, and cerebellum
[Astrocytes](/entities/astrocytes): Moderate expression
Oligodendrocytes: Present, supports myelination
[Microglia](/cell-types/microglia-neuroinflammation): Lower expression

Regional Distribution

Cerebral [cortex](/brain-regions/cortex): High in pyramidal neurons
[Hippocampus](/brain-regions/hippocampus): CA1-CA3 and dentate gyrus
[Cerebellum](/brain-regions/cerebellum): Purkinje cells and granule cells
Corpus callosum: High in oligodendrocytes
Spinal cord: Motor neurons

Role in Neurodegenerative Diseases

Hereditary Spastic Paraplegia (SPG63)

AMPD2 mutations cause autosomal recessive SPG63, one of the "thin corpus callosum" HSP subtypes[@novarino2014][@morelli2021]:

Clinical Features

Early-onset progressive spasticity in lower limbs
Thin corpus callosum on MRI
Variable cognitive impairment
Peripheral neuropathy (in some cases)
Developmental delay

Molecular Mechanisms

Loss of AMPD2 enzymatic activity
Elevated AMP/ATP ratio
Impaired mTORC1 signaling
Energy failure in corticospinal neurons
Axonal degeneration

AMPD2 Mutations

Over 30 pathogenic variants have been identified:

Genotype-Phenotype Correlation[@zhang2022]

Missense mutations: Variable phenotype
Truncating mutations: Typically severe
Null alleles: Complete loss of function

mTORC1 Signaling Dysregulation

AMPD2 critically regulates mTORC1 through the AMPK pathway[@zhang2023][@chen2022]:

Energy Sensing

AMPD2 activity → IMP production → regulates AMP/ATP ratio

AMP/ATP ratio → activates AMPK

AMPK activation → inhibits mTORC1

Pathophysiological Implications

AMPD2 deficiency leads to mTORC1 hyperactivation
Excessive mTORC1 causes:
Increased protein synthesis
Impaired autophagy
Altered cellular growth
Enhanced axonal degeneration

Therapeutic Implications

mTORC1 inhibitors (rapamycin, everolimus)
Gene therapy approaches
Metabolic modulators

Axonal Degeneration

AMPD2 deficiency leads to axonal pathology through multiple mechanisms[@liu2018][@tavernarakis2018]:

Energy Failure

Reduced ATP production
Impaired axonal transport
Loss of ionic homeostasis

mTORC1 Dysregulation

Enhanced protein synthesis burden
Impaired autophagy
Abnormal cytoskeletal dynamics

Mitochondrial Dysfunction

Reduced mitochondrial function
Impaired calcium handling
Increased oxidative stress

Other Neurological Conditions

Tuberous Sclerosis Complex (TSC)

AMPD2 interacts with TSC complex
Shared mTORC1 dysregulation
Potential therapeutic overlap

Alzheimer's Disease

mTORC1 hyperactivation in AD
Possible role for AMPD2
Therapeutic implications

Ischemic Stroke

AMPD2 has been implicated in stroke pathophysiology[@chang2023]:

Energy failure in ischemic tissue
Role in neuronal survival
Potential for neuroprotection

Epilepsy

Altered purine metabolism in seizures
Possible AMPD2 involvement
Metabolic therapy potential

Biological Functions

Purine Nucleotide Metabolism

The purine nucleotide cycle involves:

AMP → IMP (AMPD2-catalyzed)

IMP → AMP (AMP synthetase, in some tissues)

IMP → adenosine (5'-nucleotidase)

This cycle:

Maintains adenine nucleotide pool
Provides ammonia for aspartate synthesis
Links to de novo purine synthesis

Energy Homeostasis

AMPD2 contributes to energy balance through:

ATP maintenance: Recycling adenine nucleotides
AMPK activation: Sensing energy status
mTORC1 regulation: Balancing anabolism/catabolism

Amino Acid Metabolism

The enzyme connects to:

Aspartate biosynthesis: Via the purine nucleotide cycle
Gluconeogenesis: IMP can enter glycolysis
Amino acid recycling: From nucleotide catabolism

Therapeutic Strategies

Targeting AMPD2

Gene Therapy

AAV-mediated AMPD2 delivery
CRISPR-based approaches
Splice-switching oligonucleotides

Small Molecule Modulators

Enzyme activators
mTORC1 inhibitors
Metabolic modulators

Combination Approaches

Gene therapy + mTORC1 inhibitors
Metabolic + neurotrophic approaches
Symptomatic + disease-modifying

Preclinical Models

Interacting Partners and Pathways

Research Tools and Models

Animal Models

Complete knockout: Viable but with phenotype
Conditional knockouts: Brain-specific, neuron-specific
Knock-in: Patient-associated mutations
Humanized models: For drug testing

Cell Models

Primary neurons and astrocytes
Patient-derived iPSCs
Knockout cell lines
Organoid models

Pharmacological Tools

Activators: None yet developed
Inhibitors: Deoxycoformycin (broad)
mTORC1 inhibitors: Rapamycin, everolimus

[Purine Metabolism](/mechanisms/purine-metabolism) - Complete purine pathway
[mTORC1 Signaling](/mechanisms/mtor-pathway) - Growth regulation
[Energy Metabolism](/mechanisms/energy-metabolism) - Cellular energy
[Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosomal-pathway) - Cellular clearance
[AMPK Signaling](/mechanisms/ampk-pathway) - Energy sensing

[Hereditary Spastic Paraplegia](/diseases/hereditary-spastic-paraplegia) - HSP overview
[Alzheimer's Disease](/diseases/alzheimers-disease) - AD overview
[Parkinson's Disease](/diseases/parkinsons-disease) - PD overview
[Thin Corpus Callosum](/brain-regions/corpus-callosum) - Brain region

[AMPD1](/entities/ampd1) - Muscle isoform
[AMPD3](/entities/ampd3) - Erythrocyte isoform
[TBC1D32](/entities/tbc1d32) - TSC complex member

Future Directions and Research Gaps

Unmet Needs

Brain-penetrant AMPD2 activators
Understanding tissue-specific functions
Biomarker development
Gene therapy optimization

Emerging Areas

Gene therapy: Viral vector delivery

mTORC1 modulation: Therapeutic intervention

Metabolic therapy: Targeting energy pathways

Patient stratification: Genotype-phenotype

External Links

[NCBI Gene - AMPD2](https://www.ncbi.nlm.nih.gov/gene/271)
[UniProt - Q01469](https://www.uniprot.org/uniprot/Q01469)
[Ensembl - ENSG00000116337](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116337)
[OMIM - 102771](https://www.omim.org/entry/102771)
[GeneCards - AMPD2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=AMPD2)

References

[Novarino G et al, Exome sequencing identifies AMPD2 as a causal gene for HSP (2014)](https://pubmed.ncbi.nlm.nih.gov/25359978/)

[Zhang C et al, AMPD2 deficiency leads to impaired mTORC1 signaling (2023)](https://pubmed.ncbi.nlm.nih.gov/36932110/)

[Chen X et al, AMPD2 regulates cellular energy homeostasis (2022)](https://pubmed.ncbi.nlm.nih.gov/35012358/)

[Kim Y et al, AMPD2 mutations in hereditary spastic paraplegia (2019)](https://pubmed.ncbi.nlm.nih.gov/30860256/)

[Wang J et al, AMPD2 in purine metabolism and neurological disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32736191/)

[Baur JA et al, Resveratrol improves health of mice on high-calorie diet (2006)](https://pubmed.ncbi.nlm.nih.gov/17136086/)

[Liu Q et al, AMPD2 in adenine nucleotide catabolism and axonal degeneration (2018)](https://pubmed.ncbi.nlm.nih.gov/29336098/)

[Morelli G et al, AMPD2-related HSP: clinical and neuropathological findings (2021)](https://pubmed.ncbi.nlm.nih.gov/33738621/)

[Tavernarakis N et al, AMPD2 in axonal energy metabolism (2018)](https://pubmed.ncbi.nlm.nih.gov/29530952/)

[Bike H et al, AMPD2 and autophagy in cellular clearance (2020)](https://pubmed.ncbi.nlm.nih.gov/32684074/)

[Yang L et al, AMPD2 deficiency in iPSC-derived neurons (2021)](https://pubmed.ncbi.nlm.nih.gov/33901391/)

[Chen Y et al, Targeting AMPD2 for HSP (2021)](https://pubmed.ncbi.nlm.nih.gov/33508265/)

[Zhang L et al, AMPD2 mutations and genotype-phenotype in SPG63 (2022)](https://pubmed.ncbi.nlm.nih.gov/35022240/)

[Wang J et al, Purine metabolism dysregulation in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33838953/)

[Liu H et al, AMPD2 in brain development (2019)](https://pubmed.ncbi.nlm.nih.gov/31340055/)

[Moreno JA et al, AMPD2 and mitochondrial function in neurons (2020)](https://pubmed.ncbi.nlm.nih.gov/32801291/)

[Park J et al, AMPD2 in cancer metabolism (2018)](https://pubmed.ncbi.nlm.nih.gov/30214688/)

[Ji X et al, AMPD2 and AMPK signaling in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33419789/)

[Chang L et al, AMPD2 in ischemic stroke (2023)](https://pubmed.ncbi.nlm.nih.gov/36752642/)

[Zhao Y et al, AMPD2 deficiency and axonal transport (2022)](https://pubmed.ncbi.nlm.nih.gov/34984723/)

Pathway Diagram

The following diagram shows the key molecular relationships involving AMPD2 — Adenosine Monophosphate Deaminase 2 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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AMPD2 — Adenosine Monophosphate Deaminase 2

AMPD2 Gene

AMPD2 Gene

Overview

Gene Information

Protein Structure and Function

Enzyme Classification

Structural Features

Catalytic Properties

Expression Pattern

Tissue Distribution

Cellular Distribution in the Brain

Regional Distribution

Role in Neurodegenerative Diseases

Hereditary Spastic Paraplegia (SPG63)

Clinical Features

Molecular Mechanisms

AMPD2 Mutations

Genotype-Phenotype Correlation[@zhang2022]

mTORC1 Signaling Dysregulation

Energy Sensing

Pathophysiological Implications

Therapeutic Implications

Axonal Degeneration

Energy Failure

mTORC1 Dysregulation

Mitochondrial Dysfunction

Other Neurological Conditions

Tuberous Sclerosis Complex (TSC)

Alzheimer's Disease

Ischemic Stroke

Epilepsy

Biological Functions

Purine Nucleotide Metabolism

Energy Homeostasis

Amino Acid Metabolism

Therapeutic Strategies

Targeting AMPD2

Gene Therapy

Small Molecule Modulators

Combination Approaches

Preclinical Models

Interacting Partners and Pathways

Research Tools and Models

Animal Models

Cell Models

Pharmacological Tools

Cross-Linking and Related Pathways

Related Mechanisms

Related Diseases and Proteins

Related Genes

Future Directions and Research Gaps

Unmet Needs

Emerging Areas

See Also

External Links

References

Pathway Diagram